PROJECT SUMMARY Psychopathology is a very serious public health burden that not only affects adults, but also many children and adolescents. To better understand this devastating problem, the scientific community has focused its efforts on pinpointing the earliest developmental origins of psychopathology. A considerable literature now implicates prenatal stress as a critical determinant of poor psychological functioning in childhood and beyond. However, knowledge about whether the timing of prenatal stress differentially influences the development of child psychopathology is virtually unknown. Gaining such knowledge is the long-term goal of our research. This proposed project ?piggybacks? on our current RO1-funded project (NICHD grant # R01HD085990) that is following a cohort of 335 women oversampled for life stress, with data collection starting at pregnancy week 15 until 6 months postpartum. We are conducting a granular assessment of pregnancy stress (measured weekly by maternal report) with the goal of understanding critical periods during fetal life when stress derails later infant behavioral and physiological stress responsivity. The overall objective of this new RO1 project is to follow this cohort into the child's preschool years. Specifically, in Aim 1 we will determine how the differential timing of prenatal stress influences behavior problems and psychopathology measured at age 4, how differences in self-regulation (an important precursor of mental health functioning) mediates the relationship between prenatal stress and psychopathology at age 4, and how these relationships differ between boys and girls. Aim 2 will test a host of postnatal risk factors (e.g., poor maternal mental health, poverty, intimate partner violence) and resilience factors (e.g., sensitive parenting, coping skills) as moderators of the effects of timing of prenatal stress on behavior problems and psychopathology at age 4. Importantly and uniquely, postnatal stress (mother and child) is assessed also in a fine-grained manner by every 3 month assessments from age 6 mos to 4 years. Finally, in Aim 3 we will use an exploratory statistical approach, machine learning, to detect which relatively small epochs of stress in postnatal life (measured every 3 months) interact with small epochs of prenatal stress to maximally influence child behavior problems and psychopathology. This project is innovative in its highly multimethod approach (e.g., behavioral observation, salivary analytes, laboratory tasks), its granular assessment of chronic and episodic prenatal and postnatal stressors, and the novel statistical approaches used to determine which epochs of stress are most relevant for psychopathology. This highly significant research will be the first longitudinal, prospective, multi-method study of how differential timing of prenatal stress influences the development of psychopathology, as mediated by child self-regulation and moderated by postnatal environmental factors. Thus, this study is critical for understanding how early child development sets the stage for psychopathology and will lead to increased understanding of the developmental epochs to be targeted for preventative interventions.